1. Field of the Invention
This invention relates to 2-{[2-(substituted amino)ethyl]sulfonyl}ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidates, pharmaceutical compositions containing them, their pharmaceutical use, and their preparation and intermediates in their preparation.
2. Description of the Related Art
U.S. Pat. No. 5,556,942 [and PCT Publication No. WO 95/09865] discloses compounds of the formula
and their amides, esters, and salts, where:L is an electron withdrawing leaving group;SX is —S(═O)—, —S(═O)2—, —S(═NH)—, —S(═O)(═NH)—, —S+(C1-C6 alkyl)-, —Se(═O)—, —Se(═O)2—, —Se(═NH)—, or —Se(═O)(═NH)—, or is —O—C(═O)—, or —HN—C(═O)—;each R1, R2 and R3 is independently H or a non-interfering substituent;n is 0, 1 or 2;Y is selected from the group consisting of
where m is 1 or 2; andAAc is an amino acid linked through a peptide bond to the remainder of the compound.
The compounds are stated to be useful drugs for the selective treatment of target tissues which contain compatible glutathione S-transferase (GST) isoenzymes, and simultaneously elevate the levels of granulocyte macrophage progenitor cells in bone marrow. Disclosed embodiments for L include those that generate a drug that is cytotoxic to unwanted cells, including the phosphoramidate and phosphorodiamidate mustards.
One of the compounds has the formula
It is referred to in the patent as TER 286 and named as γ-glutamyl-α-amino-β-((2-ethyl-N,N,N,N-tetra(2′-chloro)ethylphosphoramidate)sulfonyl)propionyl-(R)-(−)-phenylglycine. This compound, later referred to as TLK286, has the uninverted CAS name L-γ-glutamyl-3-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]sulfonyl]-L-alanyl-2-phenyl-(2R)-glycine. As the neutral compound, its recommended International Nonproprietary Name is canfosfamide; and as its hydrochloride acid addition salt, its United States Adopted Name is canfosfamide hydrochloride. Canfosfamide and its salts are anticancer compounds that are activated by the actions of GST P1-1, and by GST A1-1, to release the cytotoxic phosphorodiamidate mustard moiety.
In vitro, canfosfamide has been shown to be more potent in the M6709 human colon carcinoma cell line selected for resistance to doxorubicin and the MCF-7 human breast carcinoma cell line selected for resistance to cyclophosphamide, both of which overexpress GST P1-1, over their parental cell lines; and in murine xenografts of M7609 engineered to have high, medium, and low levels of GST P1-1, the potency of canfosfamide hydrochloride was positively correlated with the level of GST P1-1 (Morgan et al., “Tumor efficacy and bone marrow-sparing properties of TER286, a cytotoxin activated by glutathione S-transferase”, Cancer Res., 58, 2568-2575 (1998)).
Canfosfamide hydrochloride is currently being evaluated in multiple clinical trials for the treatment of ovarian, breast, non-small cell lung, and colorectal cancers. It has demonstrated significant single agent antitumor activity and improvement in survival in patients with non-small cell lung cancer and ovarian cancer, and single agent antitumor activity in colorectal and breast cancer. Evidence from in vitro cell culture and tumor biopsies indicates that canfosfamide is non-cross-resistant to platinum, paclitaxel, and doxorubicin (Rosario et al., “Cellular response to a glutathione S-transferase P1-1 activated prodrug”, Mol. Pharmacol., 58, 167-174 (2000)), and also to gemcitabine. Patients treated with canfosfamide hydrochloride show a very low incidence of clinically significant hematological toxicity.
PCT Publication No. WO 95/09865 also discloses intermediates that are compounds of the formula
and their amides, esters, and salts, where:L is an electron withdrawing leaving group;S+ is S or Se;S* is —S(═O)—, —S(═O)2—, —S(═NH)—, —S(═O)(═NH)—, —S+(C1-C6 alkyl)-, —Se(═O)—, —Se(═O)2—, —Se(═NH)—, or —Se(═O)(═NH)—, or is —O—C(═O)—, or —HN—C(═O)—;each R1, R2 and R3 is independently H or a non-interfering substituent;n is 0, 1 or 2;Y is selected from the group consisting of
where m is 1 or 2; andAAc is an amino acid linked through a peptide bond to the remainder of the compound.
U.S. Pat. No. 6,506,739 discloses compounds of the formula
where:X is a halogen atom;Q is O, S, or NH; and R is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or is R′CO—, R′NHCO—, R′SO2—, or R′NHSO2— where R′ is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl; orR-Q together is chlorine;and their salts,as antitumor agents.
US Patent Application Publication No. 2005/0267075 [and PCT Publication No. WO 2005/118601] discloses compounds of the formulae
where:each R is independently hydrogen, C1-6 alkyl, or —CH2CH2X, where each X is independently Cl, Br, C1-6 alkanesulfonyloxy, halo-C1-6 alkanesulfonyloxy, or benzenesulfonyloxy optionally substituted with up to three substituents selected from halo, C1-3 alkyl, halo-C1-3 alkyl, C1-3 alkyloxy, or halo-C1-3 alkyloxy, provided that at least two R's in each phosphorodiamidate group are —CH2CH2X;R1 is optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; andR2 is optionally substituted alkanediyl, optionally substituted heteroalkanediyl, optionally substituted arenediyl, optionally substituted arenedialkyl, optionally substituted heteroarenediyl, or optionally substituted heteroarenedialkyl,and their salts,as antitumor agents.The compound of the formula
is disclosed as compound 16A on page 19 of US Patent Application Publication No. 2005/0267075.
U.S. Patent Application No. 60/588,436, laid open with the publication of US Patent Application Publication No. 2005/0267075 and PCT Publication No. WO 2005/118601, discloses the compounds of the formulae
as compounds 13AA and 14AA on page 26.
Jain et al., “Sulfonyl-containing aldophosphamide analogues as novel anticancer prodrugs targeted against cyclophosphamide-resistant tumor cell lines”, J. Med. Chem., 47(15), 3843-3852 (2004), discloses a series of sulfonylethyl phosphorodiamidates of the formula
The compounds are said to spontaneously liberate phosphoramide mustards via beta-elimination, and to be more potent than the corresponding phosphoramide mustards against V-79 Chinese hamster lung fibroblasts in vitro. Some of the compounds were said to show excellent in vivo antitumor activity in CD2F1 mice against the P388/0 (wild) and P388/CPA (cyclophosphamide-resistant) leukemia cell lines.
It would be desirable to develop chemically and pharmaceutically simple (easy to synthesize and formulate) anticancer drugs having an efficacy and safety as good or better than canfosfamide.
The disclosures of the documents referred to in this application are incorporated into this application by reference.